Pharmaceutical formulations

ABSTRACT

The residence time in the human stomach of pharmaceutical, gastric controlled release, solid units can be increased significantly if the units have a density that is much higher than normal. A preferred oral dosage form according to the invention comprises a capsule or other dosage form having a dimension above 2 mm and that contains one or more of the said units. The density of each unit is preferably at least 2.5 and usually at least 2.7 g/ml and can conveniently be achieved by including at least 50% by weight of a weighting agent such as barium sulphate.

The present invention relates to an oral, solid, pharmaceutical dosageform suitable for oral administration to humans and that will permitcontrolled release of a pharmaceutically active ingredient into thestomach, and optionally also into the upper intestine, over a prolongedperiod.

An oral, solid pharmaceutical dosage form comprises one or morepharmaceutical units and each of these units comprises pharmaceuticallyactive ingredient and carrier including binder.

If the units are small, e.g., below 2 mm in size, the dosage form willcontain a large number of the units Typically the dosage form is acapsule and the individual units can be small pellets.

If the unit is large, e.g. a tablet above 5 mm in size, the dosage formmay consist of a single tablet or other unit.

Selection of the binder (including its manner of application) determinesthe rate of release of the active ingredient from within each unit. Forinstance if the binder is readily soluble in gastric juices the unitwill disintegrate rapidly upon entry to the stomach, givingsubstantially immediate release of all its active ingredient. If thebinder (which may be a matrix binder or, more usually, a coating aroundthe unit) is a gastric controlled release binder it will not permitdisintegration upon entry to the stomach but will instead permitpermeation, at a preselected time and rate, of active ingredient intothe gastric juices. This makes the active ingredient available withinthe stomach and also within the upper intestine into which the stomachfluids are expelled If the binder is an enteric binder it preventsrelease of active ingredient within the stomach but instead permitsrelease only at the higher pH conditions that prevail in the upperintestine. Thus enteric units do not release active ingredient into thestomach.

Accordingly by appropriate selection of the binder it is possible tovary widely the period and location over which the active ingredient isreleased, but it may be difficult or impossible to combine bothprolonged release and optimum utilisation of active ingredient. If therelease is too slow then the unit will be discharged from the chosenlocation, or even from the body, before full release of the activeingredient. If release is too fast it is necessary to administer anotherdosage form soon after the previous dose, in order to maintain prolongedavailability of the active ingredient in the chosen environment.

In addition, units which are quickly expelled from the stomach may beexpelled from the body before all the active ingredient has beenreleased, which also wastes the active compound.

A particular problem is that it is difficult to maintain prolonged drugavailability in the stomach or upper intestine since the unit or unitsare expelled from the stomach with food or fluid, often quite quicklyafter swallowing. Attempts have been made to prolong gastric residencetime, e.g., by using dosage forms that rely on size or swellability fordelaying expulsion from the stomach, but these are not entirelysatisfactory and can incur the risk of causing blockages.

The difficulties of achieving predetermined availability of activeingredient within the stomach are made worse by the fact that theresidence time of a unit in the stomach varies according to whether thepatient is in the fed or fasted state. For instance there is a tendencyfor a controlled release tablet to pass through the stomach very muchfaster if the patient is fasting than if the tablet is administeredafter food. This effect can therefore completely overwhelm thecontrolled release effect that is desired by choice of the appropriatecontrolled release binder.

There is therefore an urgent need to provide some entirely new mechanismby which it is possible to provide prolonged release of an activeingredient within the human stomach.

The density of conventional tablets and pellets is usually about 1.0 to1.5 g/ml. Most components of the pellets and tablets have densities inthis range or less. Some components are heavier but in practice arealways used with other, lighter, components such that the final densityof the pellets or tablets is within the conventional range. For instancealuminium oxide is incorporated by a gel precipitation technique in, forinstance, GB No. 1,590,573 but always in amounts and with componentssuch that the resultant products have a typical, relatively low,density.

Robens at the "Symposium on the Characterisation of Porous Solids July1978, University of Neuchatel" described the manufacture of dosage formsby precipitation of alumina in the presence of drug, impregnation ofporous alumina with drug, mixing of porous alumina with drug andpressing alumina with drug powder and examined the effect of theresultant microporous structure. He gave no detailed information as tohow to make solid dosage forms and there was no suggestion that acontrolled release binder should be used. So far as we are aware, hisporous alumina systems have not been utilised and their density wouldpresumably be very low, because of their high porosity.

For many years consideration has been given to the effect of density onthe time of passage of solid particles through the digestive tract. Forinstance Hoelzel in "The Rate of Passage of Inert Materials through theDigestive Tract" in Am. J. Physiol, 92, 1930, pages 466 to 497 showedthat the time of passage through the digestive tract of humans was about25 hours for food having density 0.9 to 1.6 g/ml, about 80 hours forsteel ballbearings having a density of about 7.7 g/ml and about 82 hoursfor bent silver wire having a density of 10.53 g/ml.

Trace elements are administered to cows by positioning in the ruminantstomach of the cow a heavy and large bolus (typically having a dimensionabove 50 mm) containing the trace element in a controlled releasebinder. The bolus if of a size such that it remains in the stomach forseveral weeks and the binder is such as to permit very slow release ofthe trace element gradually over this period. Although this isappropriate in a ruminant digestive system, it is clearly whollyinappropriate for the digestive system of humans where grave concernwould be expressed at the possibility of an orally administeredpharmaceutical unit remaining in the digestive system for more than afew days. For instance there would be serious concern at the possibilityof blockages or obstructions being created within the digestive system.

The effect of density on the rate of gastric emptying of non-digestibleparticulate solids in dogs having chronic duodenal fistulas is discussedin Gastroenterology (1985) 89 805-13. Some of the results arecontradictory. They include indications that particles of 0.015 mm emptyat the same rate as particles of 1 mm, and that spheres with densitiesof below 1, or with densities of above 1, empty more slowly than sphereshaving a density of 1. The highest density that is examined is 2 g/ml.The spheres do not have controlled release properties.

There have also been many studies on the effect of the density ofpharmaceutical units on their transit time through the humangastrointestinal tract. In J. Pharm. Pharmac. (1978) 30 690-692,Bechgaard et al report that pellets having a density of 1.6 g/ml have asignificantly greater total intestinal transit time than pellets of 1.0g/ml in ileostomy patients. The authors query whether the intestinaltransit time of pellets in ileostomy subjects is comparable to that ofhealthy subjects and comment that a diameter of 1.5 mm must be regardedmaximal for a true multiple unit formulation.

Similar work is reported by Bechgaard in U.S. Pat. No. 4,193,985. Inthis patent, gastric controlled release pellets for capsules are formedhaving different densities so that any one capsule contains controlledrelease pellets having a range of densities. The highest density that ismentioned is 3.4 g/ml. However only pellets with densities up to 1.6g/ml are tested in vivo, again in ileostomy patients. The resultsindicated that the density differences affect the rate of travel ofpellets through the intestine. The patent proposes that a single capsulecontains pellets of different densities and states that "obviously acombination of lighter and heavier units in a multiple-units dose hasthe effect of further dispersing the units along the gastro-intestinaltract". At least 25% by weight of the units should have a specificweight at least 25% above the specific weight of other units in thecomposition.

Bechgaard and other authors have since reported that increasing thedensity does not increase human gastrointestinal transit time.

In J. Pharm. Pharmac. (1985) 37 718-721, Bechgaard et al produceevidence that they acknowledge is in direct contradiction to theirearlier findings, referred to above; they show that there is nosignificant difference in transit time for ileostomy patients ofparticles having density 0.9 g/ml and 1.96 g/ml.

In "Radionuclide Imaging in Drug Research" Croom Helm, London, (1982)294-296, Bogentoft et al describe experiments in healthy volunteers. Theresults indicate that an increase in density of pellets from 1.24 to1.81 g/ml decreases transit time.

At the 1986 European Capsule Technology Symposium Vienna, October 1986,Wilson and Washington in "Scintigraphic Studies of the Behaviour ofCapsules in the Gastro Intestinal Tract" stated that "multiparticulatesgiven with food empty (from the stomach) with the liquid and digestedfood" and that once material has entered the small intestine "mostphysical factors, such as density, appear to be unimportant".

In Pharm. Res. (1986) 3: 208-213 Davis states in a conclusion to studiesusing pellets of densities 0.94 g/ml and 1.96 g/ml or single units ofdensity 1.2 g/ml "the use of density as a means of altering the gastricresidence time of pharmaceutical dosage forms (multiple and singleunits) has little or no value. The major factor determining the gastricemptying of single units is the presence of food". This is confirmed byKaus in Pharmaceutical Research, (1987) 4(1) 78.

It should be noted that these last three articles were published afterthe priority date of this invention. Taken as a whole, the literatureclearly indicates that at and after the priority date of the inventionit was considered that (a) increasing the density of small units up to1.96 g/ml does not give any predictable increase in humangastro-intestinal transit time or human gastric residence time, (b) thehuman gastric residence time of tablets is dependent primarily uponwhether they are administered in the fed or fasted state, and (c) smallunits will empty from the stomach relatively quickly both when fed orfasted.

In AU-A-No. 46570/85 and EP No. 0173210A, the disclosure of U.S. Pat.No. 4,193,985 is discussed and it is proposed to provide a pelletformulation in which the pellets have a density of 1.4 to 2.4 g/ml, adiameter of 0.2 to 1.8 mm and a coating or other binder that isresistant to gastric juice (i.e., the binder is an enteric binder) It isstated that the pellets preferably have a density of 1.5 to 1.8 g/ml.The pellets are preferably administered in combination with uncoatedactive ingredient so that the uncoated material is available immediatelyand the enteric coated material will release active ingredient only inthe intestine.

There will be no release of the active ingredient within the stomachfrom the enteric coated material, and this is confirmed by the fact thatthe enteric materials that are specifically described are all entericmaterials that are resistant to gastric juices. For instance Eudragit(registered trade mark) grades L and S that are recommended in thepatent are materials that, according to the manufacturers data sheet,are insoluble and impermeable in natural gastric juices (in contrast toEudragit RS, which is permeable). This patent therefore does notcontribute to the need for an improved way of providing prolongedrelease of an active ingredient within the human stomach.

We have now surprisingly discovered that the human gastric residencetime of gastric controlled release units is increased by increasing thedensity of the units, provided the density is sufficiently high. Itseems that in all the recent studies on the effect of density on transitor residence time, the pharmaceutical units always had a density thatwas too close to the conventional density, and as a result increasedgastric residence time was not observed.

An oral, solid, pharmaceutical dosage form according to the inventionhas a minimum dimension of at least 2 mm and is suitable for oraladministration to humans and comprises at least one gastric controlledrelease unit comprising a pharmaceutically active ingredient and apharmaceutically acceptable carrier that includes a gastric controlledrelease binder that will permit controlled release of the activeingredient from the controlled release unit while in the stomach, andthe said controlled release unit, or each said controlled release unithas a density of at least 2 g/ml.

The invention also includes a method of making a pharmaceutical dosageform having a minimum dimension of at least 2 mm by combining apharmaceutical active ingredient with sufficient of a weighting agent togive the dosage form a density of at least 2 g/ml and with sufficient ofa gastric controlled release binder to permit controlled release of theactive ingredient from the unit while the unit is in the human stomach,and if necessary combining a plurality of the units into apharmaceutical dosage form.

The pharmaceutical dosage form must have a dimension of above about 2 mmsince dosages smaller than this are inconvenient and ineffective. Forinstance an individual pellet of U.S. Pat. No. 4,193,985 does notconstitute a pharmaceutical dosage form If the controlled release unitwithin the dosage form is relatively large, for instance a tablet, thenthe dosage form may contain, and often consist of, a single controlledrelease unit. Often, however, the dosage form comprises a plurality ofthe said controlled release units, in which event substantially all thesaid controlled release units in the dosage form must have the defineddensity.

For a useful increase in human gastric residence time to occur, it isessential that the density is above about 2 g/ml. The precise value atwhich large increases in residence time become apparent may vary to someextent from subject to subject and may depend also on, for instance, thesize of the dosage form In general, the residence time increases withincreasing density above about 2 g/ml and so although values of at leastabout 2.1 or preferably at least about 2.3 g/ml can give a usefulincrease in residence time, best results are achieved with most subjectswhen the density is above about 2.5, and preferably above about 2.7,g/ml. For instance densities in the range about 2.8 to about 3 g/mloften given a particularly convenient combination of residence time andother properties. The density can be up to about 4 g/ml or more, e.g.,up to about 6 g/ml, but it is generally unnecessary for it to be aboveabout 3.5 g/ml.

When the pharmaceutical unit is a relatively large tablet (e.g., havinga dimension above 5 and generally above 10 mm), the time of dischargefrom the stomach has conventionally been thought to be influencedgreatly by whether the tablet is administered during fasting or withfood, discharge being much faster when administered during fasting. Bythe invention the use of a relatively large tablet of the specified highdensity results in delayed discharge when administered with food and,especially, when administered during fasting. Thus when the unit is arelatively large tablet the invention can result in the residence timebeing less dependent on whether the tablet is administered with food orduring fasting.

When the dosage form contains a plurality of relatively small units, ifthese units are of conventional density and conventional pellet size,e.g., 1 to 1.4 mm, conventionally they have been thought to emptysubstantially continuously from the stomach, e.g., as if they werefluid. We find however that the onset of emptying, the half-time ofemptying (i.e., the time at which half the pellets have emptied) and thecompletion of emptying can all be increased significantly by theinvention substantially irrespective of whether the dosage form is takenwith food or during fasting. Also the increase is obtained even if thepatient is fed drinks or snacks and expulsion of the units is often onlycompleted when the subject anticipates or is eating a full meal Forinstance the onset and half-time of gastric emptying are often increasedby at least 30 minutes and frequently more than 1 hour or, expressed asa percentage of the corresponding time for pellets of conventionaldensity, by at least 10% and often at least 20% and often up to 70% oreven 100%.

These percentage increases also apply to the time at which gastricemptying of small or large units in the invention is completed andtypically this time is at least about 1/2 hour or 1 hour longer than thetime for corresponding units of conventional density. The increase inresidence time is often up to about 11/2 or 2 or even 3 hours. Forinstance the final gastric emptying time for such units conventionallyis often in the range about 21/2 hours (when fasted) to about 31/2 hours(when fed) and by the invention each of these values can easily beincreased by a value of from about 1 to about 2 hours.

Accordingly, the invention can result in significantly increased gastricresidence time and the residence time can be less influenced by whetherthe dosage form is administered with food or when fasted.

The active ingredient is released from each of the said controlledrelease units within the stomach at a rate and time that can bepreselected and controlled by appropriate choice of the controlledrelease binder, in generally known manner. For instance release mayoccur in the stomach only after a predetermined residence time.Alternatively release can occur throughout most or all of the residencewithin the stomach.

Any active ingredient that is not absorbed within the stomach passeswith fluids from the stomach into the top of the small intestine, andabsorption of active ingredient may occur there and possibly also in thesubsequent parts of the gastrointestinal tract. Similarly, after theunit has been expelled from the stomach, release of active ingredientmay occur in the intestine. Thus by the invention it is possible toprolong the availability of active ingredient within the human stomachfrom, e.g., 3 hours to up to 5 or even 6 hours, and to prolong itsavailability in the top of the small intestine.

Since each unit can be of otherwise conventional shape, size andcomposition, its use does not incur toxicological problems and thereappears to be no risk that the unit might be trapped in thegastro-intestinal tract. This is therefore a significant advantage oversize-exclusion compositions. Total expulsion from the body can beexpected within conventional times of e.g., 1 to 5 days.

The increased residence time in the stomach, and thus the increasedperiod of availability of active ingredient within the stomach (orwithin the stomach and the top of the small intestine), means that thenumber of times a dosage form has to be administered to a subject inorder to achieve substantially uniform availability of the activeingredient can be reduced. For instance a dosage form that at presenthas to be administered four or more times a day may need to beadministered, in the invention, only two or three times a day, and aform that needs to be administered three or more times a day may nowneed to be administered only twice (or even once) a day.

The dosage form must have a size and shape such that it can beadministered orally to humans and yet it must have a minimum dimensionabove about 2 mm in order that it can be handled easily and can containsufficient active ingredient to be useful.

The weight of each dosage form is generally below about 3 g, typicallyin the range about 0.3 or 0.5 up to about 2 g, for example up to 1.5 g.The amount of active ingredient in each dosage form is usually less thanabout 1 g and often less than 0.25 g. It can be as low as about 0.0001g, for instance if it is a prostaglandin or other material that isactive at very low dosages, but is often at least about 0.01, andusually at least about 0.1, g.

The dosage form can be a sachet or other package containing a pluralityof the said units and which can be emptied on to food or a liquid foradministration, but preferably the dosage form is one that can beswallowed whole in which event it must have a size and shape thatpermits its oral administration, as a whole, to humans. Typicallytherefore it has a maximum dimension of up to about 25 mm, generally inthe range about 5 or 10 mm up to about 25 mm. Its minimum dimension isusually less than about 10 mm, typically about 2 or 3 mm up to about 10mm.

For instance the dosage form may be a capsule, for instance asubstantially cylindrical or ovoid capsule having a length of about 5 to25 mm and a lesser diameter of not more than about 10 mm. The capsulecan contain a single unit but generally contains a plurality of units.The capsule can be formed in known manner from gelatin or other materialthat will dissolve or otherwise decompose to release the units in thestomach or before it reaches the stomach.

Alternatively the dosage form can be a single tablet having a maximumdimension of about 5 to 25 mm, often a diameter of about 5 to 15 mm. Thetablet can consist of a single controlled release unit or it can be acachet or disintegratable tablet comprising a plurality of the saidunits bonded by a carrier which disintegrates after swallowing, oftenwithin the stomach, to release the units. Although tablets that arepharmaceutical dosage forms according to the invention preferably haveconventional tablet shape, with a length less than half the diameter, itcan be convenient for them to have unusual shapes, e.g., solidcylinders, hollow cylinders or rings. Appropriate selection of the shapecan optimise the rate of release of the active ingredient during theprolonged residence in the stomach.

The dosage form is preferably in the form of a capsule or adisintegratable tablet or cachet containing a plurality of the saidcontrolled release units. The said controlled release units preferablyhave a mean dimension of at least about 1 mm and preferably all theunits have a dimension of at least about 1 mm. If the units are toosmall then, even if they have very high density, they are liable to beemptied from the stomach with fluid. The size at which useful resultsare best achieved may vary from subject to subject and may depend, forinstance, on the nature of the subject's pyloric sphincter. Whilst somesubjects may obtain useful increase in residence time if the units havea size as low as, for instance, about 0.8 or even about 0.5 mm, for mostsubjects rather larger dimensions are desirable for optimum results tobe achieved. As an example of a size that is much too small, we haveobserved that particles having a size of 5 microns are treated by thestomach as a fluid, substantially irrespective of density.

Best results are achieved when the said unit has a density of at leastabout 2.5 g/ml, preferably at least about 2.7 g/ml, and a mean dimensionof at least about 1 mm.

Preferred dosage forms comprise a plurality of the units in the form ofpellets having a mean maximum dimension below about 2 mm, preferably inthe range about 1 to about 1.7 mm, most preferably about 1.2 to about1.4 mm. The dosage form will then contain a large number of suchpellets, typically above about 50. The pellets may have a shape and formtypical of pellets that are conventionally used in multiple-unit drugcapsules, typically being rod-shaped or, preferably, substantiallyspherical.

Alternatively the capsule or disintegratable tablet can contain asmaller number of larger heavy controlled release units, for instancetablets having a diameter above about 2 mm, typically in the range about3 to 10 mm. Preferably such tablets have a diameter from about 3 to 5 or6 mm. Their length is generally less than their diameter, for instancebeing less than half the diameter and typically in the range about 1 to3 mm. These small tablets may be packed within a capsule ordisintegratable tablet, for instance with a plurality of the tabletsbeing stacked coaxially one upon the other within a capsule ordisintegratable tablet. The solid dosage form may then contain at leasttwo of these tablets, e.g., two to ten tablets. A capsule or otherdosage form may contain one or more of the heavy controlled releasetablets and a plurality of smaller heavy, controlled release units.

The dosage form may contain pharmaceutical units additional to the saidheavy gastric controlled release unit or units. For instance it maycontain gastric controlled release units containing a differentpharmaceutically active ingredient and which may have any chosendensity, preferably (but not necessarily) of the value chosen in theinvention. Thus the dosage form may be designed to provide conventionalgastric transit time for gastric controlled release units of onepharmaceutical active ingredient and the prolonged gastric residencetime of the invention for gastric controlled release units of adifferent pharmaceutical active ingredient.

The dosage form can, in addition, contain units that are not providedwith a gastric controlled release binder. For instance it mayadditionally include enteric units of any desired density, which thusrelease their active ingredient only in the intestine. It may includeunits that are not provided with a gastric controlled release or entericcoating, and which thus permit substantially immediate release of theactive ingredient after administration. These various units may containthe same active ingredient as the defined controlled release units ofthe invention or a different active ingredient. The dosage form mayinclude gastric controlled release units that have a high density butthat are of two or more different types. For instance the differenttypes may contain different active ingredients or may have differentgastric controlled release binders. A unit may contain a blend of activeingredients. If there is a plurality of controlled release units of anyparticular pharmaceutical active ingredient then effectively all thosegastric controlled release units containing that active ingredientshould have the specified high density so as to ensure that there isprolonged availability of that active ingredient within the stomach andthat there is maximum utilisation of the active ingredient.

The or each gastric controlled release unit, irrespective of whether itis a relatively large unit that can serve as a dosage form or whether itis one of a plurality of smaller controlled release units, comprises aselected pharmaceutically active ingredient (or a mixture of suchingredients) and a pharmaceutically acceptable carrier that includes agastric controlled release binder that will permit controlled release ofthe active ingredient from the unit while in the stomach, and optionallythat will additionally provide subsequent release within the intestine.The gastric controlled release binder may consist of a matrix binderwhich bonds the other components of the unit together in such a way asto control release but preferably the gastric controlled release bindercomprises a coating around the unit. It may then be unnecessary to haveany additional binder, or there may be a conventional matrix binder.

Known materials for use as conventional matrix binder are generallypolymers. They may be synthetic polymers but usually are naturalpolymers or derivatives, for instance starch or, preferably, celluloseor its derivatives. The preferred material is microcrystallinecellulose, which may incorporate a small amount of cellulose derivativesuch as sodium carboxymethyl cellulose or other polymer to aid in themanufacturing process. Normally the matrix binder is relativelyinsoluble in water.

The gastric controlled release binder, that is present either as acoating or as a matrix binder or both, may be selected from any of theconventional controlled release binders that will permit controlledrelease of the active ingredient at the desired time and rate. It can,for instance, be formulated to permit gradual release only after apredetermined residence time in the stomach. Generally however it isformulated in conventional manner to permit gradual, but substantiallyimmediate, release e.g., from within 15 to 45 minutes afteradministration to the stomach. Often the binder is such as to permitrelease to be sustained for at least three hours within the stomach, andmay be such as to permit release to continue after the unit is expelledfrom the stomach.

Such binders are well known and generally comprise hydrophobic acrylicpolymers or cellulose derivatives, vinyl polymers and other highmolecular weight natural polymer derivatives or synthetic polymers.Preferred film-forming gastric controlled release binders are ethylcellulose or acrylic ester polymers that are substantially free ofanionic groups and which preferably contain a small proportion ofcationic groups, e.g., a copolymer of ethyl acrylate and methylmethacrylate. Suitable materials are well known and include the productsold under the trade name Eudragit RS 100. Preferably release issubstantially independent of pH.

The controlled release coating or other binder may optionally compriseother pharmaceutically acceptable materials which improve the propertiesof the coating or binder, such as plasticisers, anti-adhesives,diffusion-accelerating or retarding substances, colourants, opacifiersor fillers. For example a plasticiser known to work well with ethylcellulose is acetyltributyl citrate.

Any controlled release coating is typically 10-100 μm thick. The filmmay be applied by spraying the binder dissolved or dispersed in asolvent system, onto a moving bed of the units. Most widely used methodsare the fluidised bed and pan coating systems, the preferred methodbeing the fluidised bed method.

Since the other components of the unit will generally have a density notmore than about 1.5 g/ml, it is generally necessary to include in theunit a suitable amount, usually at least 50% by weight of the unit, of apharmaceutically acceptable weighting agent, which is generally aninorganic compound, for example comprising a salt, oxide or hydroxide ofa metal (including blends such as ferrum redactum).

The weighting agent is usually in particulate form. It generally has adensity of at least 2.5 g/ml preferably at least 3.0 g/ml, morepreferably at least 3.5 g/ml, generally more than 4.0 or sometimes morethan 5.0 g/ml. Usually the density is less than 10 g/ml and often needbe no more than 6.0 g/ml. Examples of suitable particulate materials areshown in the following table which shows the density of the powders ing/ml.

Magnesium trisilicate: 3.2

Magnesium oxide: 3.6

Aluminium oxide: 4.0

Bismuth subcarbonate: 6.3

Bismuth subnitrate: 4.9

Zinc oxide: 5.6

Titanium dioxide: 3.9-4.2

Calcium ferrite: 5.1

Ferrous oxide: 5.7

Barium sulphate: 4.5

Ferric oxide: 4.5

The most suitable powders are barium sulphate, ferric oxide, ferrumredactum, titanium dioxide and aluminium oxide or hydroxide, calciumcarbonate, barium phosphate, bismuth phosphate, calcium aluminosilicate,zirconium silicate, calcium phosphate, silicon carbide, and magnesiumcarbonate. The preferred weighting agent is generally barium sulphatebut another very satisfactory material is ferrous oxide or ferrumredactum.

The amount of weighting agent is selected to give the desired densityand this in turn depends, in part, on the packing density and thus theparticle size and shape of the weighting agent and the other components.Often the amount of the weighting agent is above 50 or 60%, usuallybelow 90 or 95%, based on the dry weight of the unit, with particularlygood results often being achieved with values of around 70 or 75 up to90% by weight.

The total amount of controlled release binder is generally at leastabout 0.1%, and often about 1 to 5%, by weight of the unit. It can be upto or even above 10% but it is generally unnecessary for it to be above30%. The total amount of binder (controlled release and other binder) isgenerally below 50% and usually below 30% of the dry weight of the unit.

In order that the units have the desired high density the amount ofweighting agent should be as high as possible and typical units compriseabout 50 to 90% weighting agent, about 2 to 30% binder (the amount ofcontrolled release binder often being about 0.1 to 10% and the amount ofother binder being 0 to about 30%), about 0.0001 to 45% (usually below20%) active ingredient, about 0 to 45% (usually about 0 to 20%) othercarrier components.

When the controlled release unit is a tablet having a large diameter,e.g., above 10 mm, it is often desirable that the carrier shouldcomprise material that will dissolve or otherwise react in the stomachso as to cause disintegration or erosion of the tablet within thestomach if it is retained there for more than six hours, e.g.,disintegration should occur at not less than six hours and not more than72 hours after swallowing. For instance when the dosage form is in theform of a tablet having a size of 10 to 25 mm, preferably 10 to 15 mm,the carrier may comprise material that is soluble in the gastric juices.

As the binder is usually sufficiently permeable to gastric fluid, theuse of a weighting agent that is soluble in hydrochloric acid, forinstance aluminium hydroxide, barium sulphate, calcium carbonate,calcium phosphate or magnesium carbonate can be a useful way ofachieving disintegration of the tablet after prolonged residence in thestomach.

The carrier of the units may comprise other conventional additives suchas lubricants, fillers, stabilisers and/or colourants.

Each unit may comprise a homogeneous or non-homogeneous blend of theactive ingredient and the weighting agent and any matrix bindercomponent. For instance each unit may have a core of weighting agentcovered by a shell of active ingredient or vice versa or it may beformed of a blend of the active ingredient and the weighting agent.

The units may be made by known techniques selected according to theshape and size of the desired units. For instance tablets may be made byconventional tableting methods or by extrusion of a paste of theingredients, drying the paste and breaking or chopping it intoappropriate lengths as it is extruded or dried.

Any initial blend of weighting agent and active ingredient is usuallymade by physically mixing the two ingredients but sometimes can be madeby coprecipitation.

Relatively small units, e.g., below about 2 mm, can be made byconventional pelletising methods. For instance the pellets may be madeby using crystals of the active agents as cores and then coating thecores with the dense material and binder. Alternatively the densematerial and optional binder may be formed into heavy cores which arethen coated with the active ingredient and with binder.

Another method of producing pellets is by gel precipitation in which asolution or sol of an inorganic compound containing a gelling agent andthe therapeutically active compound and comprising a weighting agent isgelled by dropping into a precipitating solution or vice versa or by useof a gaseous precipitating agent. Such methods are further described inGB No. 1590573 and J. Pharm. Pharmac. (1984) 36 1-6 but have to bemodified (as do all known methods) by the use of sufficient of a chosenweighting agent to give the desired high density.

Related methods in which gels containing active substances are producedby a sol-gel transformation are described in GB No. 1590574. The gelpellets generally include a matrix binder and then may be formulatedsuch that the release of active ingredients is sufficiently controlledin the absence of a coating, or a coating may be applied.

However, the preferred method for forming the pellets or other units isto make a mixture of the weighting agent and the active ingredient andmatrix binder and then to form the mixture into the units. Generallysome water is added to the mixture to aid pelletisation. The optimumamount of water that is included in the mixture during pelletisation orother blending or shaping step is dependent upon the binder, theweighting agent and the active ingredient used. In general it is in therange 5 to 50%, preferably 20 to 40%, by weight based on the totalweight of dry ingredients.

Usually the pellets are formed by extruding the moist mass to formcylinders. These may be cut to length or allowed to break to randomlengths and dried to give cylinders having diameters typically of about0.4 to 2 mm, generally about 1 to 2 mm. The length of the cylinders isgenerally above about 1 mm. Instead of providing dried pellets in theform of cylinders, the pellets are preferably made by spheronization,that is to say by spheronizing extruded moist cylinders. Spheronizingmay be by rolling or tumbling the extruded moist cylinders butpreferably it is carried out as described in "Pharmacy International"May 1985 pages 119-123. The mixture of dense material, activeingredient, water and binder, is extruded to form cylinders preferablyof uniform diameter and of a suitable, though not necessarily uniform,length. The cylinders are then rounded in a spheronizer which comprisesa horizontal rotating plate having grooves on its upper surface within avertical cylinder. The cylinders are left in the spheronizer until theyare rounded, this generally taking up to 15 minutes.

After formation to the desired shape, the pellets are dried, generallyin a fluidised bed drier using hot air. Any surface coating may beapplied within the drier and is generally applied by spraying a solutionor suspension of the coating material onto the surface of the pellets.

The pellets or other units may be formulated into capsules of a solublematerial in known manner. The weight of pellets in each capsule will bedependent upon the size of the capsule, density employed, and the sizerange and therefore number that each capsule may contain For example,1.2-1.4 mm diameter pellets of density 2.9 g/ml may give a range ofweights of 0.84 g-0.9 g within a typical capsule.

Although we believe the invention is of wide applicability to theadministration of a wide range of pharmaceutical active ingredients,particular importance of the invention is that it provides, for thefirst time, an improved way of administering drugs that are alimentarytract and metabolic products, cardiovascular products, blood andclotting products, CNS and other neurological products, H₁ antagonistsand products having anti-viral activity and, in particular, it providesa very convenient way of administering low dosages of prostaglandins.

The invention is of particular value when the ingredient is to beabsorbed in the stomach, e.g., for providing local treatment of stomachdisorders or when the ingredient is to be absorbed in the upper part ofthe intestine. Especially important are those ingredients absorbed byactive transport. The invention can result in reduction of localirritation of the gastrointestinal tract and permits increase in theinterval between dosage administrations, thereby improving patientcompliance and stabilising plasma levels. This is particularly importantfor drugs with short half-lives and/or a narrow therapeutic range.

One class of useful drugs are drugs for the alimentary tract andmetabolic products such as drugs for preventing or treating pepticulcers, antacids, antiflatulent products, stomatological drugs,gastrointestinal, anti-spasmodic or anticholinergic products,anti-emetics and antinauseants, anti-diarrhea drugs, laxatives,cholalogues and hepatic protective products, antiobesity preparations,digestives, antidiabetic drugs, systemic anabolic drugs, appetitestimulants and other metabolic products, including essential amino acidsupplements, rectal and colonic drugs and other gastrointestinal drugs.

Examples of antipeptic ulcer drugs are H₂ antagonists, such as thecompounds disclosed in GB No. 2,075,007 especially sufotidine, thecompounds disclosed in GB No. 2,023,133 especially lamptidine, and thecompounds disclosed in GB No. 2,047,238 especially loxtidine, as well ascimetidine and ranitidine.

Some prostaglandins also have antiulcer properties and are of particularvalue for use in the present invention. Examples of prostaglandins whichcan be used are compounds described in GB Nos. 2,097,397, 2,217,406,2,174,702 and EP No. 160,495. Other antipeptic ulcer treatments includeomeprazole, carbenoxolane, liquorice and sucralfate.

Examples of antispasmodic drugs include atropine sulphate, propanthelinebromide, mebeverine and dicyclomine. Examples of antiemetic/antinauseadrugs include indole derivatives such as the compounds disclosed in GBNo. 2,153,821, EP Nos. 219,193, 210,840 and 191,562 as well as1,2,3,9-tetra-hydro-3-[(2-methylimidazol-1-yl)methyl]-9-methyl-4H-carbazol-4-one,cyclizine, cinnarazine, domperidone, prochlorperazine and hyoscine.Antidiarrhoea products include diphenoxylate hydrochloride, loperamideand codeine phosphate. Sodium cromoglycate and sulfasalazine aresuitable rectal/colonic drugs and metoclopramide is a suitablecholalogue.

Another class of preparations for which the invention can be usedincludes vitamins, minerals and tonics. Vitamins which may be includedare vitamins B₂, B₁₂ and B₆, minerals include iron, zinc, selenium andother trace elements. The invention can also be used for other oralnutrition products such as essential amino acids.

Another class of products useful in the invention is cardiovascularproducts, including drugs for cardiac therapy, including antiarrhythmicproducts, hypotensives (anti-hypertensives), including centrally actingand other antihypertensives, diuretics, products for cerebro- andperipheral vasotherapies, including vasoconstrictors and vasodilators,antihaemorrhoidal and antivaricose products, betablockers, includingcardio selective betablockers, calcium antagonists, ACE-inhibitors andother enzyme inhibitors and enzyme stimulants, and other cardiovascularproducts.

Suitable antiarrhythmic products include amiodarone, flecainide,verapamil, procainamide and quinidine. Suitable antihypertensive agentsinclude methyldopa and clonidine. Diuretics include chlorothiazide andhydrochlorothiazide. Vasodilators include isosorbidedinitrate/mononitrate. Cerebral vasoconstrictors, for instance for thetreatment of migraine, include the compounds disclosed in GB No.2,162,522, especially3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide.Betablockers include propanolol, labetalol, oxprenolol, acebutolol andmetoprolol. Calcium antagonists (blockers) include nifedepine. Twoexamples of ACE-inhibitors are captopril and enalapril.

Another class of drugs for which the invention is suitable is blood andclotting products, including anticoagulants and antiplatelet products,fibrinolytic products, antihaemorrhagic products, antianaemia productsand hypolipidaemic drugs. Antiplatelet products include dipyridamole.Antianaemia products include iron salts and folic acid.

The invention can also include dermatological products such asantifungal agents and antiacne agent.

Another class of drugs useful in the invention are genito-urinaryproducts and sex hormones, including gynaecological antiinfectives andother gynaecological products, sex hormones including contraceptives andurological products. Another class includes hormones, excluding sexhormones, for example systemic corticosteroids, drugs for thyroidtherapy and other systemic hormones.

Another class of products useful in the invention is antibiotics,including systemic antibiotics, systemic antifungal products, systemicsulphonamides, and other anti-infectives and, especially, systemicantiviral agents.

Antivirals may be for the treatment of human retrovirus infections suchas AIDS, or herpes infections such as herpes simplex, herpes zoster orcytomegalovirus infections, as well as treatment of viruses related tocancer of the cervix or other cancer-causing viruses, or other viralinfections. Examples of antiherpes antiviral products include compoundsdescribed in GB No. 1,523,865, especially acyclovir, and gancyclovir,and zidovudine (AZT) and other compounds described in EP No. 196185 areexamples of anti-AIDS products.

Another class of products for use in the invention includes anticanceragents, including alkylating agents, antimetabolites, anticancerhormones, immunodulators and other cytostatic products.

Antiparasitic agents can also be used in the invention, e.g.,anthelmintics.

The invention is also of use for musculoskeletal products, includingantirheumatics, muscle relaxants, antigout preparations andantiinflammatory enzymes. Examples of preparations for gout treatmentinclude allopurinol, colchicine and probenecid.

Another class of products useful in the invention is that ofneurological products, including analgesics, antiepileptic products,antiParkinson treatment, psycholeptic agents, including neuroleptics,hypnotics, sedatives and tranquilisers, and psychoanaleptic drugs,including antidepressants, psychostimulants, nootropes and cerebralvasodilators.

Suitable analgesics include morphine, codeine, dihydrocodeine andmethadone as well as indomethacin and diclofenac sodium. Suitableantiepileptics include carbamazepine, chlorazepam and phenobarbitone.Antiparkinson preparations include L-dopa, amantidine, bromocryptine andprocyclidine Suitable psycholeptic drugs include triazolam, diazepam,lorazepam, chlordiazepoxide, clobazam and oxazepam. Suitablepsychoanaleptics include chlorpromazine, lithium salts, haolperidol,amitryptyline, perohenazine, clomipramine, promazine and mianserin.

Another class of products useful in the invention are respiratoryproducts, including antiasthmatics including bronchodilatory andantiallergic products Examples of suitable antiasthmatic products aresalbutamol, terbutaline, aminophylline and theophylline.

H₁ antagonists are another class of products of particular use in theinvention Examples of H₁ antagonists include triprolidine,chlorpheniramine, brompheniramine and other arylalkylamine derivativessuch as the compounds disclosed in EPA No. 85959, especially(E)-3-[6-[(E)-3-(1-pyrrolidinyl)-1-(p-tolyl)-lpropenyl]-2-pyridyl]acrylic acid (acrivastine); phenothiazine derivates such as thecompounds disclosed in EPA No. 117302; dibenzoxepin anddibenzocycloheptene derivatives such as those disclosed in EPA No.214779; terfenadine; and astemizole.

Other drugs which can be used in the invention are preparations fortreatment of coughs and colds and sensory products includingantiglaucoma products, opthalmological products and otological products.

Throughout this specification, and in the following examples, density ofpharmaceutical units is measured by an air comparison pycnometer.

The following examples illustrate the invention:

EXAMPLE 1

Mixtures of powders of heavy materials as indicated and binder, in eachcase microcrystalline cellulose containing 15% sodiumcarboxymethylcellulose, in the quantities indicated were mixed withwater to produce a mass. The mass was extruded to form cylinders havingdiameters in the range 1.2-1.4 mm and lengths of about 2-15 mm. Thecylinders were worked in a spheronizer until spheres having diameters ofabout 1.2-1.4 mm were formed. The spheres were dried in a fluidised beddrier.

The following table shows the heavy material and the relative amounts ofingredients, and the density of the pellets after drying.

    __________________________________________________________________________                           Water in                                                                      extruded                                                       Amount w/w                                                                           Amount binder                                                                         mass. w/w                                                                             Density                                                based on                                                                             w/w based on                                                                          based on                                                                              dried                                          Weighting                                                                             total of                                                                             total of dry                                                                          total weight                                                                          pellets                                        agent   dry powder                                                                           powder  of dry powders                                                                        g/ml                                           __________________________________________________________________________    a Al.sub.2 O.sub.3                                                                    80     20      25      3.0                                            b Mg(SiO.sub.2).sub.3                                                                 80     20      40      2.9                                            c BaSO.sub.4                                                                          80     20      25-27   3.2                                            d BaSO.sub.4                                                                          75     25      28-30   3.0                                            e MgO   75     25      36      2.7                                            f MgO   80     20      32      2.8                                            g Ca.sub.3 (PO.sub.4).sub.2                                                           75     25      40      2.7                                            h Fe.sub.2 O.sub.3                                                                    75     25      38      3.2                                            i Fe.sub.2 O.sub.3                                                                    80     20      35      3.4                                            __________________________________________________________________________

These pellets were uncoated and were then converted to controlledrelease pellets by the application of a controlled release coating ofethyl cellulose in an amount of 2.5% by weight based on the total weightof pellets, and which reduced the density of the pellets by about 0.1g/ml.

EXAMPLE 2

Pellets are made as in example 1 containing 80% barium sulphate, 19.9%microcrystalline cellulose binder and 0.1% riboflavin. The amount ofwater in the extruded mass was 25-27% based on the total weight ofweighting agent, binder and riboflavin. The density of the dried pelletswas 3.2 g/ml. When coated with about 2% by weight controlled releasecoating of ethyl cellulose or Eudragit RS 100 the density is reduced toabout 3.1 g/ml. A gelatin capsule is filled with a large number of thesepellets to a weight of about 0.85 g.

Similarly, the 0.1% riboflavin can be replaced with any of the othertherapeutic active ingredients mentioned above and the pellets can bepacked in capsules or sachets or can be bonded by starch into adisintegratable tablet.

EXAMPLE 3

A mixture of aluminium oxide 80%, microcrystalline cellulose 17% andriboflavin 0.5%, is granulated with an aqueous solution of polyvinylpyrrolidone (PVP) to yield a final content of 1% of PVP. The granulesare dried and mixed with 1% of magnesium stearate and compacted to give200 mg tablets of 10 mm diameter containing 1 mg of riboflavin and adensity greater than 3.0 g/ml. The tablets are coated with about 6 mg ofa gastric controlled release coating of ethyl cellulose or Eudragit RSto give a density of at least 2.7 g/ml.

EXAMPLE 4

50 mg tablets, having a diameter of about 4 mm are made from the samemix as in Example 3 and are coated as in that Example. Each contains0.25 mg riboflavin. Four such tablets are packed in a gelatin capsule.

EXAMPLE 5

To demonstrate the rate of transit of the units through the stomach,heavy pellets of density 2.8 to 2.9 g/ml produced as in Example 1d werelabelled with 99m-Technetium and coated with ethyl cellulose, the finaldensity of the spheres being 2.8 to 2.9 g/ml Spheres made by the samemethod but containing lactose instead of the heavy material werelikewise labelled and coated to give pellets having a density of 1.5g/ml.

A sample of the light or heavy pellets was fed to healthy volunteers whowere each either fasted or had received a light breakfast and theradioactivity within the stomach region of interest was observed usingthe technique of gamma scintigraphy using two gamma cameras one at thefront of the volunteer and the other at the back for accuracy.

The time of initiation of gastric emptying, the half-time (the time atwhich half the pellets had been emptied) and the time at which gastricemptying was effectively completed was recorded and the values averaged.The results are shown in the following table.

    ______________________________________                                                Light      Heavy                                                              (minutes)  (minutes)                                                                              % Increase                                        ______________________________________                                        Initiation                                                                    Fed       116          199      71                                            Fasted    101          141      40                                            Half-Time                                                                     Fed       181          269      49                                            Fasted    125          204      48                                            Completion                                                                    Fed       236          288      22                                            Fasted    152          217      43                                            ______________________________________                                    

This clearly demonstrates the much longer residence time of the heavypellets than the light pellets, both when fed and fasted.

When the experiment was conducted with pellets having a density of 2.5g/ml, the initiation, half-time, and completion values were always lessthan those quoted in the table above for the heavy pellets, but weregreater than the values for the light pellets.

We claim:
 1. An oral, solid, pharmaceutical dosage form that is acapsule or disintegratable tablet and that has a minimum dimension of atleast 2 mm and that is suitable for oral administration to humans andthat comprises a plurality of controlled release units each comprising apharmaceutically active ingredient and a pharmaceutically acceptablecarrier that includes gastric controlled release binder that will permitcontrolled release of the active ingredient from the controlled releaseunit while in the stomach, and in which each said controlled releaseunit has a density of at least 2.5 g/ml.
 2. A dosage form according toclaim 1 in which the said density is at least 2.7 g/ml.
 3. A dosage formaccording to claim 1 in which the said density is below 6 g/ml.
 4. Adosage form according to claim 1 in which the or each said controlledrelease unit has a mean dimension of at least about 1 mm.
 5. A dosageform according to claim 1 in which each said unit has a mean dimensionof about 1 to about 2 mm.
 6. A dosage form according to claim 1 in whicheach said unit is spheronized pellets having a mean diameter of about 1to about 2 mm.
 7. A dosage form according to claim 1 having a maximumdimension of about 5 to about 25 mm and a minimum dimension of belowabout 10 mm.
 8. A dosage form according to claim 1 in which the saidcarrier of each said controlled release unit includes also about 50% toabout 95% by weight of the said unit of a pharmaceutically acceptableweighting agent having a density of at least about 3.0 g/ml.
 9. A dosageform according to claim 1 in which the said carrier of each saidcontrolled release unit includes also about 50% to about 95% by weightof the said unit of a pharmaceutically acceptable weighting agent whichcomprises barium sulphate or ferrous oxide.
 10. A dosage form accordingto claim 1 in which the controlled release binder comprises a controlledrelease coating around each said controlled release unit.
 11. A dosageform according to claim 1 in which the active ingredient is selectedfrom alimentary tract and metabolic products, cardiovascular products,blood and clotting products, neurological products, H₁ antagonists, andproducts having antiviral activity.
 12. A dosage form according to claim1 in which the active ingredient is a prostaglandin.
 13. A method ofprolonging the release of an active ingredient within the human stomachwhen administering orally a solid pharmaceutical dosage form that is acapsule or disintegratable tablet and that has a minimum dimension of atleast 2 mm and that comprises a plurality of controlled release unitseach comprising the said ingredient and a pharmaceutically acceptablecarrier that includes a gastric controlled release binder that willpermit controlled release of the active ingredient from the unit whilein the stomach, the method comprising incorporating into each saidcontrolled release unit at least 50% by weight of a weighting aid havinga density of at least about 3 g/ml and thereby increasing the density ofeach said unit to above 2.5 g/ml.
 14. In a method of releasing an activeingredient within the human stomach by administering orally a solidpharmaceutical dosage form that is a capsule or distingratable tabletand that has a minimum dimension of at least 2 mm and that comprises aplurality of controlled release units each comprising a pharmaceuticallyactive ingredient and a pharmaceutically acceptable carrier thatincludes gastric controlled release binder that will control release ofthe active ingredient from the controlled release unit while in thestomach, the improvement which comprises prolonging the release of theactive ingredient within the stomach by using, as each controlledrelease unit, a unit have a density greater than 2.5 g/ml.
 15. Themethod according to claim 14, in which each controlled release unit hasand a mean dimension of not more than about 2 mm.
 16. In an oral solidpharmaceutical dosage form that is a capsule or disintegratable tabletand that has a minimum dimension of at least 2 mm and that is suitablefor oral administration of humans and that comprises a pharmaceuticallyactive ingredient and a pharmaceutically acceptable carrier thatincludes gastric controlled release binder that will permit controlledrelease of the active ingredient from the controlled release unit whilein the stomach, the improvement which comprises each said controlledrelease unit having a density of at least 2.5 g/ml, whereby retention inthe stomach of all the units is prolonged.
 17. The oral dosage form ofclaim 1 in which each controlled release unit has and a mean diameter ofnot more than about 2 mm.
 18. The oral dosage form of claim 16 in whichthe density of each controlled release unit is the same.
 19. A dosageform according to claim 1 in which the density of each controlledrelease unit is the same.
 20. A method according to claim 13 in whichthe density of each resulting controlled release unit is the same.
 21. Amethod according to claim 14 in which the density of each controlledrelease unit is the same.